Amyloidosis is a family of diseases which occur both in humans and in experimental animals. The usual method of induction in mice is by parenteral injection of 5-10% casein daily for 4 weeks or more. During studies on the oral induction of tolerance with casein we discovered that mice raised on normal laboratory mouse chow are "naturally" orally tolerized to casein since most mouse chows contain casein as a protein source. With respect to the induction of amyloidosis by parenteral casein, this is of some interest since there have been studies indicating that mice on casein free diet are less susceptible. In addition, in a preliminary experiment we found that the relatively resistant A/J strain have a significantly higher primary response to immunization with casein than CBA/J or C57B1/6 mice which are very susceptible. This difference is antibody response might be related to a difference in the degree of orally induced tolerance, and if so, might also suggest a relationship between oral tolerance to casein (induced and maintained by the dietary content of casein) and susceptibility to casein induced amyloidosis. In order to study this possibility we will raise casein free mice and compare their susceptibility to casein induced amyloidosis with mice raised on a normal diet. If casein free animals are less susceptible, we will assess the effect of adding casein to their diet. In addition, SAA, an acute phase reactant in the serum which is immunologically related to amyloid AA protein, shows a rapid increase in injection of parenteral casein in animals on a normal diet. We will examine the SAA response in casein free animals. Finally, macrophage activation and T and B cell function have been reported to be altered in the development of casein induced amyloidosis. We will re-examine these parameters of immunologic function in casein free animals to determine if these changes are related to orally induced tolerance to casein. These studies may lead to a better understanding of the murine model of amyloidosis, and thus suggest new avenues of research into the pathogenesis of the human disease as well.